Prostatic cancer is a highly intractable disease which affects an increasing number of men, and now has surpassed lung cancer as the most frequently diagnosed cancer in men in the United States. Prostatic cancer is often curable if the tumor is confined to a small region of the gland and found at an early stage, and is destroyed by radiation or surgically removed in its entirety. Unfortunately, a great many prostatic cancers have already infiltrated surrounding tissue or have metastasized to remote sites, frequently the bone marrow, before initial detection. In this instance, radiation and other therapies may be more palliative than curative.
Once it was recognized how androgen dependent both normal development of prostatic cells and tumor growth were, androgen deprivation therapy appeared to offer a systemic mode of treatment. In fact, a dramatic remission in symptoms and tumor regression are observed in instances of castration or hormonal drug suppression, for which Charles Huggins won the Nobel Prize in 1966. However, the effects of androgen deprivation were temporary, and the cancers soon relapse with emergence of a new androgen independent cell type, which is unusually aggressive and resistant to all treatment modalities. In such instances, it is only the relatively slow progression of the disease in older patients and the intervention of other morbid processes, that permitted such patients to escape the inevitable outcome of the cancer. For a general review of issues in conventional treatment of prostate cancer, see "Prostate Cancer Working Group", Coffey, D. S., Chair, Cancer Res., 51: 1498 (1991).
Androgen deprivation is a useful therapy. Among the androgen suppressive drugs licensed by the FDA, are Stilphostrol, which is a phosphorylated nonsteroidal estrogen, and Lupron, a synthetic nonapeptide analog of GnRH. The relapse of temporary remission and emergence of androgen independent malignant cells is variable, and hormonal therapy offers many patients sustained relief for a time. It is not understood how the tumor cells overcome their androgen dependence, or if they do, since it has not been ruled out that, at least in some instances, the androgen independent cells arise from a different precancerous clone.
Nevertheless, new treatments are clearly needed. In the last few years, there has been a significant trend towards detection of prostate cancer more frequently and at earlier stages, brought about largely by the availability of more sensitive and accurate tests for the quantitation of Prostate Specific Antigen (PSA). Concomitantly, more is known about the molecular biology of prostatic tumor expression, although how these molecular discoveries can be translated into effective therapies is not clear. For example, the androgen dependence of the early malignant cells focusses attention on the AR gene and the SRD5A2 gene. Abnormal gene expression can result from gene amplification (AR) leading to altered expression, and from genetic polymorphisms (SDR5A2) associated with high risk individuals.
Karp, et al., Cancer Res., 56: 5547 (1996) describes a number of potential therapies based on some of the molecular observations. For example, targeting antiandrogen/antiestrogen mechanisms with inhibitors of steroid 5alpha-reductase (Finansteride, etc., or steroid aromatise (Exemestane, etc.) may offer therapeutic possibilities. Also, drugs that suppress cellular proliferation, such as E-Cadherin mimetics, PD 153035 (through EGF receptor interaction), or Fluasterone (inhibition of nucleotide synthesis), may be effective where the molecular abnormality in a given tumor is diagnosed.
Monoclonal antibodies have been used in oncology as both diagnostic tools and therapeutic adjuncts. Unconjugated antibodies have been used in patients with acute leukemias (see more recent review). An antiganglioside monoclonal antibody has been used in some patients with melanomas to some advantage (see Houghton, et al., 85: 1242 (1985)). For conjugated antibodies, monoclonals bearing radionuclides have been evaluated. .sup.131 I and .sup.90 Y have been most extensively studied, although these are associated with some toxicity. Other antibody conjugates include biologic toxins (such as ricin, S. exotoxin, etc.) and chemotherapeutic drugs (such as methotrexate, or Doxorubicin).
A number of prostate-reactive antibodies have been produced and evaluated to various degrees. The most extensively studied antibody is designated 7E11 and reacts with PSMA. Radiolabelled 7E11 reacts specifically with prostate cancer cells, and has proven useful as a diagnostic agent in patients with occult recurrence of prostate cancer, as described in Kahn, et al., J. Urol., 152: 1490 (1994), and elsewhere. The use of this antibody (7E11-C5.3) in phase I clinical trials, labelled with 111In, is discussed in Monoclonal Antibodies 2: Applications in Clinical Oncology, ed. A. A. Epenetos, Chap. 32, Chapman & Hall Medical: 1993.
This antibody, however, has a number of limitations. It recognizes an intracellular rather than a surface epitope, thus having limited value in targeting viable cells. Thus, there exists a great need for monoclonal antibodies which have the desired specificity, and target epitopes of stably expressed antigen molecules on the surface of the target tumor cell.
The immune mechanisms leading to destruction of target tumor cells are partially understood. A population of cytolytic T cells have been identified which carry the CD8+ antigenic determinant on their surfaces. These cells require CD4+ helper lymphocytes for activation, which is a complex event mediated by antigen processing and presentation in association with the major histocompatibility complexes. Antigen processing assures that only cells targeted to the tumor antigens will be activated
Monoclonal antibodies directed to various markers on subpopulations of T lymphocytes have been used to activate immune effector cells. OKT3 antibody administered by injection, for example, meets with CD3, and can cause a whole array of immune effects including IL-2, TNF-alpha, and IL-6 release, tissue damage, and either activation or suppression of T cell activity. More recently, OKT3 specificity has been combined with a antitumor specificity in a bispecific antibody. Link, et al., Blood, 81: 3343 (1993) showed that a bispecific antibody having one arm of OKT3 and the other arm directed to a B-cell malignant antigen was able to induce cytotoxicity of target tumor cells. Interestingly, the T-cell activation was without regard to the natural specificity of the T cell, and required the presence of the tumor cells. Thus, in the simultaneous binding of tumor cell and effector cell by the same antibody, the T cells are effectively recruited from the general T cell population, and retargeted to destroy the tumor cells.
It has also been shown by Weiner, Int. J. Cancer, Supplement 7, 63 (1992) that the action of the bispecific antibody is enhanced by coadministration of IL-2, so that combinational therapy resulted in management of a 100 to 1000 times greater tumor load than with the anti-tumor monoclonal antibody alone. Alternatively, the co-stimulus observed in the use of the bispecific antibody may be provided through binding of the Fc domain of the antibody to the Fc monocyte receptor, which in turn provide the co-stimulus, possibly through binding of the B7 family of membrane proteins to CD28. Preactivation ex vivo of cytotoxic T cells with co-administration of bispecific F(ab') has also been reported (Mezzanzanice, et al., Cancer Res., 51:5716 (1991).